Dr. Bass has had extensive training in metabolism related biomedical research beginning with work as an M.D., Ph.D. student at the Medical College of Pennsylvania under the direction of Drs. Julian Marsh and Edward Fisher. There the role of tissue macrophages in the secretion of apolipoprotein E and cholesterol uptake was investigated. Subsequently, the P.I. completed residency in Internal Medicine and a Fellowship in Endocrinology under the Clinical Investigator Pathway of the American Board of Internal Medicine. For the past 3 years the P.I. has worked with Drs. Donald Steiner and Graeme Bell at the University of Chicago where he investigated the biosynthesis and structure of the insulin receptor. This work provided the foundation for the present application. The insulin receptor is a large and complex glycoprotein that undergoes extensive posttranslational modification important in its translocation and expression. Yet, the molecular details underlying the biosynthetic pathway remain inadequately understood. Recently, Dr. Bass has shown that nascent insulin receptors associate with three resident endoplasmic reticulum (ER) molecular chaperones, calnexin (Cnx), calreticulin (Crt) and binding protein (BiP) and blocking these interactions reduces the cell surface expression of the receptor. The aim of this project is to dissect the molecular mechanisms by which these chaperones effect insulin receptor biogenesis. The approach is to use pulse-chase labeling, coimmunoprecipitation with antibodies to the receptor and to the three chaperones, in combination with pharmacologic and genetic methods to disrupt receptor-chaperone interactions. The experiments will involve site-directed mutagenesis, transfections, and analytic techniques such as sucrose velocity sedimentation and confocal microscopy. These studies will illuminate the quality control mechanisms that regulate delivery of functional receptors to the cell surface. The University of Chicago provides an outstanding environment for basic diabetes-related research. The Department of Medicine has long fostered the careers of young scientists. The ability of the P.I. to interact with the sponsor, Dr. Steiner, in addition to Drs. Graeme Bell, Susan Lindquist and other excellent scientists at the University of Chicago will promote his continued development as an independent researcher.